Influenza virus is a single-stranded RNA virus in the Orthomyxoviridae family. The virus is responsible for seasonal influenza. Approximately 200,000 hospitalizations and about 36,000 deaths per year are attributable to the influenza virus. On occasion, a novel antigenic strain of influenza virus evolves to cause a pandemic. These influenza pandemics usually occur about three times per century, causing an infectious threat to human beings. Typically, the pandemics occur when novel influenza A viruses infect the human population. As examples of these pandemics, the 1918 Spanish influenza pandemic infected 25-40% of the world's population, killing twenty to one hundred million people. In 1957 and 1968, approximately one million people were killed during those pandemics. More recently, in April 2009, H1N1 influenza viruses have spread throughout the world, with an estimated 1,483,520 confirmed cases that lead to 25,174 deaths. The potential for another pandemic realizes the need for targeted therapeutic and improved prophylactic agents to battle emerging influenza viruses. H1N1 vaccines are in clinical trials in the United States, but antiviral drugs and non-pharmaceutical means of controlling infections are probably the first line defenses against the disease. Also of importance is the fact that elderly patients, infants and people with compromised immune systems may have a more limited response to vaccination.
At this point in time, there are two options for treating influenza. One option is use of M2 ion channel blockers, such as amantadine that blocks endocytosis and cell fusion. The other option is the use of neuraminidase inhibitors such as oseltamivir and zanamivir that block viral release. However, amantadine has become very ineffective as a treatment, and oseltamivir seems to require much higher doses for treatment in murine models.
Without wishing to be bound by theory, it is believed that the identification of novel targets in the influenza viral life-cycle have resulted in novel therapeutic compounds. The criteria for the development of broad spectrum anti-virals include a specificity for virus infected cells, broad conservation among virus strains, indispensability for viral replication and the development for orally-active drug candidates. This research has led to the identification of influenza protein targets, such as PA, PB1, PB2 and nucleoproteins.
As an example of some of the early work in this targeted research, Merck scientists reported the discovery of dioxobutanoic acid and flutimide as inhibitors of the endonuclease activity of influenza RNA dependent RNA polymerase (IRdRp). The resultant work suggested the possibility that IRdRp inhibitors would be useful as anti-viral agents. Later, a small prodrug (T-705) that is converted to the ribonucleoside triphosphate was determined to be a selective inhibitor of the IRdR polymerase and is currently in Phase III clinical trials in Japan. It is the specificity of T-705 against influenza A, B and C in vivo that validates IRdRp as a promising target for developing influenza therapy. In this context, the IRdRp inhibitors are attractive targets for the development of anti-virals to treat and prevent influenza.
Therefore, there remains a need for anti-viral compounds to prevent and treat influenza virus. It is this need that has led to the identification of novel compounds and methods of treating and preventing influenza virus. These needs and others needs are met by the present invention.